The Insulin/IGF signaling (IIS) pathway is an evolutionarily conserved pathway that regulates fundamental biological processes such as development, metabolism, fecundity, cellular stress resistance and aging, in many organisms including fly and mammals. In C. elegans, IIS regulates dauer formation, longevity, fat metabolism, stress response, and innate immunity. This pathway is initiated through the Insulin-IGF receptor ortholog daf-2, which activates a phosphorylation cascade. The ultimate outcome of the signaling pathway is the phosphorylation of the forkhead transcription factor DAF-16. Phosphorylated DAF-16 is retained in the cytoplasm, functionally inhibiting the transcription of a number of DAF-16 regulated genes.

Nematodes like C. elegans can survive the harshest of environmental conditions by adopting an alternative developmental program and entering into the dauer state. Dauer stage worms are reproductively immature. Entry into or exit from dauer in C. elegans is a carefully weighted decision taking into account factors such as food availability and population density, which is measured by pheromone levels in the population. Dauer development entails metabolic changes, such as increasing fat storage, and remodeling of tissues leading to the arrest of normal developmental programs, and a significant increase in lifespan. These metabolic and physiological changes are choreographed by changes in gene expression. One gene in particular, daf-16, a homolog of the human FKHR and AFX genes, appears to play a major transcriptional regulatory role in this process. A second key gene, a receptor tyrosine kinase and insulin/IGF receptor ortholog, daf-2, negatively regulates daf-16. Mutations in daf-2 result in a Dauer consititute phenotype and an extended lifespan. The C. elegans dauer stage larvae are often equated with the IJ infective juvenile stage larvae of parasitic nematodes.

Aging in C. elegans involves measurable declines in morphology, reproduction, and behavior. Understanding the cellular and molecular processes leading to senescence in this nematode began in the early 1980s with the targeted identification of mutants with extended life spans (an AGE phenotype). These studies identified at least two key regulators of life span, DAF-2, an insulin/IGF receptor ortholog, and DAF-16, a Forkhead-related transcription factor. Since then many more genes and pathways involved in senescence have been identified. Almost all of these genes play important roles in cellular and organismal-level processes other than aging, such as dauer formation, stress response, feeding, and chemosensation. A common marker for aging in C. elegans is the accumulation of lysosomal deposits of lipofuscin, resulting in an increase in intestinal autofluorescence over time.

Programmed cell death (PCD), or apoptosis, is an integral component of C. elegans development. During development, 131 cells are fated to die by apoptosis. PCD is easily observed with Nomarski optics in the C. elegans embryo; the nucleus of the apoptotic cell becomes refractile, resembling a flat button, making C. elegans an easy model for following apoptotic cell death. PCD in C. elegans can be divided into three main phases (with participating genes): specification of which cells should live or die (ces-1, ces-2, in general); activation of the cell killing machinery (egl-1, ced-9, ced-4 and ced-3); and an execution phase where the dying cell is dismantled and removed through phagocytosis (ced-1,-2,-5,-6,-7,-10 and-12), which occurs in concert with apoptotic DNA degradation (cps-6, nuc-1). Molecular and biochemical studies in C. elegans revealed programmed cell death mechanisms conserved in humans. The regulatory pathway that controls cell death is composed of conserved cell death activators and inhibitors: EGL-1 and BH3-domain-only proteins, CED-9 and Bcl-2, CED-4 and Apaf-1, and CED-3 and caspases, in nematodes and mammals, respectively. Further the degradation of chromosomal DNA involves a mitochondrial proapoptotic endonuclease: endonuclease G (EndoG), and AIF in mammals and their orthologs CPS-6 and WAH-1 in worms.

Some chemical metals are micronutrients at low concentrations and are essential for key biological processes. At higher concentrations, these essential metals, e.g., calcium (Ca), copper (Cu), zinc (Zn), manganese (Mn), etc., can have toxic effects. Likewise, nonessential metals, even in low doses can also be toxic. Toxicity can be attributed to the metal element binding to structural proteins, enzymes, and nucleic acids, inhibiting or altering the function of the bound object. Both essential and nonessential metals are found naturally in the environment as well as in concentrated sources stemming from human activity through mining and industrial wastes; vehicle emissions; lead-acid batteries; fertilizers, paints and treated woods. Metals, in particular heavy metals such as cadmium (Cd), arsenic (As), antimony (Sb), lead (Pb), mercury (Hg), and chromium (Cr), have been shown to be able to impede or alter basic cellular functions causing severe neurological damage. C. elegans, the most abundant soil invertebrate, provides a model organism for the study of metal toxicity. As a free-living soil nematode, C. elegans is exposed to many toxins naturally present in the soil. Heavy metals such as Cd result in larval lethality and arrested development. Among its repertoire of defenses, C. elegans has a highly tuned nervous system that allow the animals to recognize and avoid toxins, for example the ADL, ASE and ASH neurons direct behaviors in response to Cu or Cd. In cases of exposure to toxic concentrations of metals, a generalized cellular stress response is activated that includes an increase in expression of a number of genes, including heat shock stress proteins such as daf-21/Hsp90, that direct cellular repair and defense. Studies of metal toxicity in C. elegans has also revealed a strong correlation between toxicity and temperature-dependent metabolic activity.

microRNA (miRNA) elements are short (20-25 nucleotides (nt)), noncoding, single-stranded RNAs that bind to complementary sequences on target messenger RNA (mRNAs), which can result in translational repression or target mRNA degradation. microRNAs are critical components of developmental timing, responses to stress, and aging. Regulating the biogenesis and metabolism of miRNAs thus has an enormous impact on the health of the organism. In the genome, miRNAs reside in intergenic regions as well as within introns and exons of protein-coding genes. miRNAs are transcribed as long primary miRNAs (pri-miRNA). These pri-miRNA transcripts form hairpin-like structures with a double stranded stem and a terminal loop. pri-miRNAs are cleaved into smaller ~65-nt long precursor miRNA (pre-miRNA) by terminal-loop binding proteins and a microprocessor complex. This complex is composed of DRSH-1/DROSHA and PASH-1/DGCR8. In humans and yeast, the pre-miRNA product is exported to the cytoplasm by Exportin-5/XPO5 and RanGTP, respectively. The closest homologs of these proteins in C. elegans include xpo-1 and Y105E8A.1/yrs-2. Once in the cytoplasm, the pre-miRNA is cleaved at the top of the terminal loop by DCR-1/DICER, producing a duplex of two mature ~22nt miRNAs.An alternative, DRSH-1/DROSHA-independent, miRNA biogensis pathway has been identified in C. elegans and Drosophila. In this pathway pre-miRNAs are created through mRNA spliced introns. These introns form Mirtron lariats, which are debranched and refolded into pre-miRNA species. Mirtron generated pre-miRNAs are exported and processed in the same way as pre-miRNAs generated through the canonical miRNA biogenesis pathway. As mentioned previously, miRNA activity functions in many biological processes and hence needs to be temporally and spatially regulated. Much of that regulation occurs at the level of miRNA biogenesis and processing through Drosha binding/associated proteins, Dicer binding proteins, or proteins that bind to pri- and/or pre-miRNAs terminal loops. These regulators control expression or activity of miRNAs on specific miRNAs or families of miRNAs. For example, DCR-1 interaction proteins, ALG-1 and ALG-2, are required for lin-4 and let-7 miRNA formation and maturation. miRNA processing can also be influenced by ADAR editing, cellular localization, proteins known to regulate transcription (such as p53, SMADs) and proteins known to regulate mRNA stability (such as KSRP).